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1.
Lancet ; 395(10227): 878-887, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-32087818

RESUMO

BACKGROUND: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke. METHODS: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018. FINDINGS: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups. INTERPRETATION: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. FUNDING: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Peptídeos/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Trombectomia , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/complicações , Proteína 4 Homóloga a Disks-Large/efeitos dos fármacos , Método Duplo-Cego , Procedimentos Endovasculares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/efeitos adversos , Peptídeos/efeitos adversos , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento
2.
Future Microbiol ; 14: 1087-1097, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31512522

RESUMO

Aim: In this work, mastoparan analog peptides from wasp venom were tested against Candida albicans and safety assays were performed using cell culture and model zebrafish. Materials & methods: Minimal inhibitory concentration was determined and toxicity was performed using human skin keratinocyte and embryo zebrafish. Also, permeation of peptides through embryo chorion was performed. Results: The peptides demonstrated anti-C. albicans activity, with low cytotoxicity and nonteratogenicity in Danio rerio. The compounds had different permeation through chorion, suggesting that this occurs due to modifications in their amino acid sequence. Conclusion: The results showed that the studied peptides can be used as structural study models for novel potential antifungal agents.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Peptídeos/farmacologia , Venenos de Vespas/farmacologia , Animais , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/efeitos adversos , Peptídeos e Proteínas de Sinalização Intercelular/toxicidade , Queratinócitos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Peptídeos/toxicidade , Venenos de Vespas/administração & dosagem , Venenos de Vespas/efeitos adversos , Venenos de Vespas/toxicidade , Peixe-Zebra
3.
Medicine (Baltimore) ; 98(7): e14571, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30762805

RESUMO

BACKGROUND: Bone fractures are a common occurrence, and, according to clinical investigations, approximately 5% to 10% of patients with fractures will suffer from delayed healing or even non-healing. The high efficacy of traditional Chinese medicine in promoting fracture healing has been fully verified over a long history of diagnosis and treatment. Traditional Chinese medicine has a long history of applying Chinese herbs to treat fractures. Cervus and cucumis polypeptide injection has been widely used to promote fracture healing after fracture surgery in clinic, but its efficacy and safety are controversial. For the above reasons, the purpose of this study is to systematically evaluate the efficacy and safety of cervus and cucumis polypeptide injection in promoting fracture healing after bone fracture surgeries and to provide a theoretical basis for the selection of appropriate treatment measures for delayed healing of patients with fractures. METHODS: A total of 8 databases were searched, including the non-Chinese-language databases PubMed, The Cochrane Library, Web of Science, and Embase and the Chinese databases Chongqing VIP Chinese Journal Service Platform (VIP), Wanfang Data Knowledge Service Platform (Wanfang Data), SinoMed and Chinese National Knowledge Infrastructure (CNKI). The databases were queried for publicly released randomized controlled trials of the effectiveness and safety of Cervus and Cucumis polypeptide injection for fracture healing after surgical treatment, and no language restrictions were imposed. The software Review Manager 5.3 was used to evaluate the quality of the selected documents, and Stata 12.0 software was used for statistical analysis. RESULTS: This review will be to assess the efficacy and safety of cervus and cucumis polypeptide injection in promoting fracture healing after bone fracture surgeries. CONCLUSION: Our study will use systematic evaluation to objectively evaluate the efficacy and safety of cervus and cucumis polypeptide injection in promoting fracture healing after fracture surgery. It will provide theoretical basis for guiding clinical practice and benefit more patients. ETHICS AND DISSEMINATION: This study is a systematic review that does not require ethical approval and meets the requirements of protocol for a systematic review and meta-analysis. At the same time, this study does not involve the recruitment of patients. All data are from published academic papers. PROTOCOL AND REGISTRATION: A protocol had been registered for this systematic review and meta-analysis in PROSPERO. (registration number: CRD42019120965).


Assuntos
Cucumis , Cervos , Consolidação da Fratura/efeitos dos fármacos , Fraturas Ósseas/tratamento farmacológico , Medicina Tradicional Chinesa/métodos , Peptídeos/uso terapêutico , Animais , Humanos , Injeções , Medicina Tradicional Chinesa/efeitos adversos , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa
4.
Dig Dis ; 37(4): 297-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30731474

RESUMO

BACKGROUND: Video capsule endoscopy provides noninvasive visualization of the small bowel, but yield is often limited by debris. At our institution, preparation with polyethylene glycol (PEG) and simethicone is used to improve visualization. AIMS: We hypothesized that linaclotide and simethicone would yield equal to better results. METHODS: We enrolled 29 subjects for the experimental regimen of linaclotide and simethicone. We maintained standard NPO status, clear liquid period, and simethicone dose. Subjects received 290 µg of linaclotide 1 h prior to capsule. We randomly selected 30 historical PEG controls. Two blinded gastroenterologists graded visualization as ideal/excellent, good, fair, or poor and measured small bowel transit time. RESULTS: Thirteen men and 16 women were enrolled with an average age of 61. There was no significant difference in exam quality between linaclotide and control. Preparation was rated as ideal/excellent or good in 19 of 28 of linaclotide and 18 of 28 PEG subjects when recorder entered the small bowel (p = 0.78, chi-square). Median small bowel transit was 192 min (linaclotide) versus 202 min (PEG), respectively (p = 0.93, t test). Three studies (1 linaclotide and 2 PEG) failed to leave the stomach; 1 linaclotide subject had recorder failure. Diagnostic yield was similar (18/29 for linaclotide and 16/30 for PEG, p = 0.50, chi-square). There were no serious side effects. No differences in age, sex, BMI, or frequency of diabetes, GERD, or gastroparesis were measured between the groups. CONCLUSIONS: Single-dose linaclotide 1 h before capsule endoscopy was equally effective when compared to PEG in terms of visualization and transit time. This trial was registered at ClincialTrials.gov, number NCT02465385.


Assuntos
Endoscopia por Cápsula , Catárticos/farmacologia , Peptídeos/administração & dosagem , Peptídeos/farmacologia , Polietilenoglicóis/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Simeticone/farmacologia , Resultado do Tratamento
5.
Expert Rev Gastroenterol Hepatol ; 13(4): 397-406, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30791771

RESUMO

BACKGROUND: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess linaclotide safety in a large, pooled Phase 3 population. METHODS: In six randomized controlled trials (RCTs), patients received linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12-26 weeks; in two long-term safety (LTS) studies, patients received open-label linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Overall, 3853 patients received ≥1 dose of linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea. CONCLUSION: These pooled analyses of patients treated for ≤104 weeks confirm linaclotide's overall safety.


Assuntos
Constipação Intestinal/tratamento farmacológico , Defecação/efeitos dos fármacos , Agonistas da Guanilil Ciclase C/uso terapêutico , Síndrome do Intestino Irritável/tratamento farmacológico , Peptídeos/uso terapêutico , Doença Crônica , Ensaios Clínicos Fase III como Assunto , Constipação Intestinal/diagnóstico , Constipação Intestinal/fisiopatologia , Diarreia/induzido quimicamente , Diarreia/fisiopatologia , Agonistas da Guanilil Ciclase C/efeitos adversos , Humanos , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/fisiopatologia , Peptídeos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Fatores de Risco , Resultado do Tratamento
6.
J Agric Food Chem ; 67(5): 1429-1436, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30628451

RESUMO

The aim of this work was to determine bioavailability and in vivo calmodulin-dependent-phosphodiesterase (CaMPDE)-inhibitory activity of six flaxseed-protein-derived peptides (AGA, AKLMS, QIAK, RWIQ, QQAKQ, and KQLSTGC) after oral administration to Wistar rats. Initial experiments tested the cytotoxicity and cellular-transport potentials of the peptides using Caco-2 cells. The cytotoxicity assay indicated that none of the six peptides had an adverse effect on the proliferation and viability of the Caco-2 cells, whereas the transport assay confirmed peptide translocation across the cell membrane. However, only two of the peptides (AGA and RWIQ) were detected in the rat serum up to 90 min postgavage, with traces of RWIQ persisting in serum 1 week after oral gavage. The six peptides inhibited plasma activity of CaMPDE with AGA (34.63%), QIAK (36.66%), and KQLSTGC (34.21%) being the most effective 30 min after gavage. In contrast, only AGA maintained significant plasma-CaMPDE-activity inhibition (44.35%) after 60 min.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/química , Linho/química , Peptídeos/química , Animais , Disponibilidade Biológica , Transporte Biológico , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Linho/genética , Humanos , Masculino , Mapeamento de Peptídeos , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Ratos , Ratos Wistar
7.
Prog Biophys Mol Biol ; 142: 10-22, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30125585

RESUMO

Therapeutic activity of antibiotics is noteworthy, as they are used in the treatment of microbial infections. Regardless of their utility, there has been a steep decrease in the number of drug candidates due to antibiotic resistance, an inevitable consequence of noncompliance with the full therapeutic regimen. A variety of resistant species like MDR (Multi-Drug Resistant), XDR (Extensively Drug-Resistant) and PDR (Pan Drug-Resistant) species have evolved, but discovery pipeline has already shown signs of getting dried up. Therefore, the need for newer antibiotics is of utmost priority to combat the microbial infections of future times. Peptides have some interesting features like minimal side effect, high tolerability and selectivity towards specific targets, which would help them successfully comply with the stringent safety standards set for clinical trials. In this review, we attempt to present the state of the art in the discovery of peptide-based antimicrobials from a design perspective.


Assuntos
Anti-Infecciosos/farmacologia , Peptídeos/farmacologia , Anti-Infecciosos/efeitos adversos , Desenho de Fármacos , Resistência Microbiana a Medicamentos , Humanos , Modelos Moleculares , Peptídeos/efeitos adversos , Conformação Proteica , Engenharia de Proteínas/métodos
8.
Am J Physiol Renal Physiol ; 316(2): F231-F240, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30353743

RESUMO

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are well-established glucose-lowering drugs for type 2 diabetes mellitus (T2DM) management. Acute GLP-1RA administration increases urinary excretion of sodium and other electrolytes. However, the renal tubular effects of prolonged GLP-1RA treatment are largely unknown. In this secondary analysis of a randomized trial, we determined the renal tubular effects of 8-wk treatment with 20 µg lixisenatide, a short-acting (prandial) GLP-1RA, versus titrated once-daily insulin glulisine in 35 overweight T2DM-patients on stable insulin glargine background therapy (age: 62 ± 7 yr, glycated hemoglobin: 8.0 ± 0.9%, estimated glomerular filtration rate: >60 ml·min-1·1.73 m-2). After a standardized breakfast, lixisenatide increased absolute and fractional excretions of sodium, chloride, and potassium and increased urinary pH. In contrast, lixisenatide reduced absolute and fractional excretions of magnesium, calcium, and phosphate. At week 8, patients treated with lixisenatide had significantly more phosphorylated sodium-hydrogen exchanger isoform 3 (NHE3) in urinary extracellular vesicles than those on insulin glulisine treatment, which suggested decreased NHE3 activity in the proximal tubule. A rise in postprandial blood pressure with lixisenatide partly explained the changes in the urinary excretion of sodium, potassium, magnesium, and phosphate and the changes in urinary pH. In conclusion, lixisenatide affects postprandial urinary excretion of several electrolytes and increases urinary pH compared with insulin glulisine in T2DM patients after 8 wk of treatment. This is most likely explained by a drug-induced rise in blood pressure or direct inhibitory effects on NHE3 in the proximal tubule.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/efeitos adversos , Túbulos Renais Proximais/efeitos dos fármacos , Peptídeos/efeitos adversos , Adulto , Idoso , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/urina , Esquema de Medicação , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peptídeos/administração & dosagem , Fosforilação , Eliminação Renal/efeitos dos fármacos , Sódio/urina , Trocador 3 de Sódio-Hidrogênio/antagonistas & inibidores , Trocador 3 de Sódio-Hidrogênio/urina , Fatores de Tempo , Resultado do Tratamento
9.
J Dermatolog Treat ; 30(6): 558-564, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30427231

RESUMO

Background: Pentasodium tetracarboxymethyl palmitoyl dipeptide-12 (PTPD-12), a newly-synthesized peptide, enhances the autophagy activity, ultimately managing inflammation. Objective: To determine the effect of a new moisturizer containing PTPD-12 as the treatment of mild-to-moderate atopic dermatitis (AD). Methods: In this double-blind, randomized, placebo-controlled trial, 43 patients with mild-to-moderate AD were randomly assigned to either the PTPD-12 or control groups. Evaluations were performed at baseline, week 2, and week 4, including SCORing Atopic Dermatitis (SCORAD) index score, corneometry, trans-epidermal water loss (TEWL), visual analog scale (VAS) for pruritus, 7-point investigator's global assessment (IGA), and collection of adverse events. Results: The PTPD-12 group showed significant improvement with respect to SCORAD score, skin hydration, TEWL, and pruritus at weeks 2 and 4 when compared with baseline. Although the control group showed significant improvement regarding the SCORAD score and skin hydration, no significant change in TEWL or pruritus was demonstrated throughout the study. The mean changes in the SCORAD index score, skin hydration, TEWL, pruritus, and number of patients with improvement in IGA were not statistically different between the two groups. Conclusion: The moisturizer with autophagy-stimulating property provides a good therapeutic option to mild-to-moderate atopic dermatitis by contributing to skin barrier restoration and control of inflammation.


Assuntos
Dermatite Atópica/tratamento farmacológico , Dipeptídeos/uso terapêutico , Peptídeos/uso terapêutico , Adolescente , Adulto , Criança , Pré-Escolar , Dermatite Atópica/patologia , Dipeptídeos/efeitos adversos , Dipeptídeos/química , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Peptídeos/efeitos adversos , Efeito Placebo , Prurido/patologia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
10.
Diabetes Obes Metab ; 21(3): 726-731, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30421545

RESUMO

Maintaining optimal glycaemic control reduces the risk of micro- and macrovascular complications in patients with type 2 diabetes. Typically, glycaemic control is based on glycated haemoglobin (HbA1c) as a measure of mean glucose concentration; however, this marker does not accurately reflect glycaemic variability (GV), which is characterized by the amplitude, frequency and duration of hypo- and hyperglycaemic fluctuations. In the present study, we analysed data from the LixiLan-O trial, which compared iGlarLixi, a titratable fixed-ratio combination of the glucagon-like peptide-1 receptor agonist lixisenatide (Lixi) and long-acting basal insulin glargine 100 units/mL (iGlar), with its individual components, and the LixiLan-L trial, which compared iGlarLixi with iGlar. The GV features that were measured were mean and SD of self-measured plasma glucose (SMPG), high blood glucose index (HBGI) and low blood glucose index, area under the SMPG curve for each patient (AUCn), mean absolute glucose (MAG) and mean amplitude of glycaemic excursions (MAGE). By week 30, iGlarLixi improved all GV markers from baseline, with no increased hypoglycaemia risk. Significant improvements were observed in SMPG, SD of SMPG, HBGI, AUCn, MAG and MAGE compared with iGlar, and in SMPG, HBGI and AUCn, compared with Lixi.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemia/prevenção & controle , Insulina Glargina/administração & dosagem , Peptídeos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Combinação de Medicamentos , Feminino , Hemoglobina A Glicada/efeitos dos fármacos , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Insulina Glargina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Estudos Retrospectivos
11.
Medicine (Baltimore) ; 97(51): e13710, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30572502

RESUMO

OBJECTIVE: We aimed to systematically evaluate the efficacy and safety of lixisenatide in patients with type 2 diabetes mellitus. METHODS: PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, Google, Web of Science and the Chinese Science Citation Database were searched up to March 2018. Randomized controlled trials determining the efficacy and safety of lixisenatide in patients with type 2 diabetes mellitus were eligible for inclusion. Two authors independently extracted the data in a prespecified Microsoft Excel spreadsheet. A meta-analysis was performed using Review Manager 5.3 software. Weighted mean difference (WMD) and relative risk (RR) together with their corresponding 95% confidence intervals (CIs) were estimated, and only the random effects model was used in order to achieve a more conservative estimate of the efficacy and safety. RESULTS: Fourteen multicenter randomized controlled trials involving 11,947 patients were eligible for inclusion. Compared to placebo, lixisenatide could more significantly reduce the level of HbA1c (WMD=-0.44; 95% confidence interval [CI] [-0.55,-0.33]), and a higher proportion of lixisenatide-treated patients achieved the HbA1c level of < 7.0% (RR = 1.89, 95% CI [1.75-2.03]) and < 6.5% (RR = 3.03, 95% CI [2.54-3.63]) than the placebo-treated patients. Lixisenatide was also associated with a significant reduction in fasting plasma glucose and 2-hour postprandial plasma glucose levels. The risks for any adverse events, gastrointestinal adverse events, and symptomatic hypoglycemia significantly increased in the lixisenatide-treatedment group compared to those in the placebo group. However, lixisenatideit did not increase the risks of serious adverse events, death, or severe hypoglycemia. CONCLUSIONS: Lixisenatide was more effective than placebo in patients with type 2 diabetes mellitus, and the mild-to-moderate adverse events were found to be tolerated during the follow-up.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Peptídeos/efeitos adversos , Peptídeos/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Theranostics ; 8(19): 5320-5335, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555549

RESUMO

Peptides are a rapidly growing class of therapeutics with many advantages over conventional small molecule drugs. Dextrorotary (D)-peptides, with increased enzymatic stability and prolonged plasma half-life in comparison with natural L-peptides, are considered to have great potential as recognition molecules and therapeutic agents. However, the in vivo efficacy of current therapeutic D-peptides is hindered by their inefficient cellular uptake in diseased tissues. Methods: To overcome physiological and cellular barriers to D-peptides, we designed a gold-based ultra-small nanocarrier coupled with polylysine (PLL) and a receptor-targeted peptide to deliver therapeutic D-peptides. Using a D-peptide p53 activator (DPA) as a proof of concept, we synthesized, functionalized and characterized gold- and DPA-based nanoparticles termed AuNP-DPA. Results: AuNP-DPA were effectively enriched in tumor sites and subsequently internalized by cancer cells, thereby suppressing tumor growth via reactivating p53 signaling. More importantly, through a series of in vivo experiments, AuNP-DPA showed excellent biosafety without the common side effects that hinder p53 therapies in clinic trials. Conclusion: The present study not only sheds light on the development of AuNP-DPA as a novel class of antitumor agents for drugging the p53 pathway in vivo, but also supplies a new strategy to use D-peptides as intracellular PPI inhibitors for cancer-targeted therapy.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Portadores de Fármacos/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Terapia de Alvo Molecular/métodos , Peptídeos/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Produtos Biológicos/efeitos adversos , Produtos Biológicos/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Portadores de Fármacos/efeitos adversos , Portadores de Fármacos/síntese química , Portadores de Fármacos/farmacocinética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Células HCT116 , Xenoenxertos , Humanos , Nanopartículas Metálicas/efeitos adversos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular/efeitos adversos , Nanomedicina/métodos , Transplante de Neoplasias , Peptídeos/efeitos adversos , Peptídeos/síntese química , Peptídeos/farmacocinética , Resultado do Tratamento
13.
Lancet Diabetes Endocrinol ; 6(11): 859-869, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30292589

RESUMO

BACKGROUND: The results of the ELIXA trial demonstrated the cardiovascular safety of lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes and acute coronary syndrome. In this exploratory analysis of ELIXA, we investigate the effect of lixisenatide on renal outcomes. METHODS: ELIXA was a randomised, double-blind, placebo-controlled trial, done at 828 sites in 49 countries. Patients with type 2 diabetes and a recent coronary artery event were randomly assigned (1:1) to a daily subcutaneous injection of lixisenatide (10-20 µg) or volume-matched placebo, in addition to usual care, until at least 844 patients had an adjudicated major adverse cardiovascular event included in the primary outcome. Patients, study staff, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary endpoints of this trial have been reported previously. Here, in an exploratory analysis of ELIXA, we investigated percentage change in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) according to prespecified albuminuria status at baseline (normoalbuminuria [UACR <30 mg/g]; microalbuminuria [≥30 to ≤300 mg/g]; and macroalbuminuria [>300 mg/g]) using a mixed-effect model with repeated measures. Time to new-onset macroalbuminuria and doubling of serum creatinine were also assessed with Cox proportional hazards models. The ELIXA trial is registered with ClinicalTrials.gov, number NCT01147250, and is completed. FINDINGS: Of 6068 patients randomly allocated between July 9, 2010, and Aug 2, 2013, baseline UACR data were available for 5978 (99%). Median follow-up time was 108 weeks. 4441 (74%; 2191 assigned to placebo and 2250 assigned to lixisenatide) had normoalbuminuria, 1148 (19%; 596 assigned to placebo and 552 assigned to lixisenatide) had microalbuminuria, and 389 (7%; 207 assigned to placebo and 182 assigned to lixisenatide) had macroalbuminuria. After 108 weeks, the placebo-adjusted least-squares mean percentage change in UACR from baseline with lixisenatide was -1·69% (95% CI -11·69 to 8·30; p=0·7398) in patients with normoalbuminuria, -21·10% (-42·25 to 0·04; p=0·0502) in patients with microalbuminuria, and -39·18% (-68·53 to -9·84; p=0·0070) in patients with macroalbuminuria. Lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo when adjusted for baseline HbA1c (hazard ratio [HR] 0·808 [95% CI 0·660 to 0·991; p=0·0404]) or baseline and on-trial HbA1c (HR 0·815 [0·665 to 0·999; p=0·0491]); point estimates were similar when adjusted for other traditional renal risk factors. At week 108, the largest eGFR decline from baseline was observed in the macroalbuminuric group, but no significant differences were observed between the two treatment groups. No significant differences in eGFR decline were identified between treatment groups in any UACR subgroup. In the trial safety population, doubling of serum creatinine occurred in 35 (1%) of 3032 patients in the placebo group and 41 (1%) of 3031 patients in the lixisenatide group (HR 1·163, 95% CI 0·741-1·825; p=0·5127). As previously reported in the ELIXA trial, the proportion of patients with renal adverse events was low (48 [1·6%] of 3032 patients in the placebo group vs 48 [1·6%] of 3031 patients in the lixisenatide group) and did not significantly differ between treatment groups. INTERPRETATION: Lixisenatide reduces progression of UACR in macroalbuminuric patients, and is associated with a lower risk of new-onset macroalbuminuria after adjustment for baseline and on-trial HbA1c and other traditional renal risk factors. FUNDING: Sanofi.


Assuntos
Síndrome Coronariana Aguda/complicações , Diabetes Mellitus Tipo 2/complicações , Nefropatias/prevenção & controle , Peptídeos/uso terapêutico , Albuminúria/complicações , Albuminúria/prevenção & controle , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/complicações , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
14.
Am J Ther ; 25(6): e670-e674, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30169374

RESUMO

BACKGROUND: Unexpected serious adverse drug reactions (sADRs) affecting patients with chronic kidney disease (CKD) who received erythropoiesis-stimulating agents were identified by study co-authors. These included pure red cell aplasia (PRCA) after administration of the Eprex formulation of epoetin or the epoetin biosimilar HX575 and fatal anaphylaxis associated with peginesatide, an erythropoietin receptor agonist. We developed and applied a structured framework to describe these sADRs, including root cause analyses and eradication efforts. METHODS: A 10-step framework termed "ANTICIPATE," focusing on signal identification, incidence, causality, and eradication guided our evaluations. RESULTS: Initial cases were identified by a hematologist (Eprex), clinical study monitors (HX575), and 4 nurses (peginesatide). The number of persons with individual ADRs was 13 PRCA cases for epoetin, 2 antibody-mediated PRCA cases for HX575, and 5 fatal anaphylaxis cases for peginesatide. Initial incidence estimates per 1000 treated persons were 0.27 for Eprex-associated PRCA, 11 for HX575-associated PRCA, and 0.38 for peginesatide fatalities. Likely causes were subcutaneous administration of epoetin formulated with polysorbate 80 (Eprex), tungsten leaching from pins included in product syringes (HX575), and inclusion of a phenol stabilizer (peginesatide). Eradication strategies included restricting Eprex administration to the intravenous route, excluding tungsten from HX575 syringes, and for peginesatide, proposed eradication was to return to single-dose vials without preservatives. CONCLUSION: Although the number of cases of each sADR was small, eradication was successful for 2 sADRs, and a proposed eradication was developed for a third sADR. The structured framework used to describe the above 3 sADRs in patients with CKD can also be used in other clinical settings.


Assuntos
Anafilaxia/epidemiologia , Hematínicos/efeitos adversos , Aplasia Pura de Série Vermelha/epidemiologia , Insuficiência Renal Crônica/complicações , Análise de Causa Fundamental/estatística & dados numéricos , Anafilaxia/induzido quimicamente , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/etiologia , Epoetina alfa/efeitos adversos , Excipientes/efeitos adversos , Humanos , Incidência , Injeções Intravenosas/efeitos adversos , Injeções Subcutâneas/efeitos adversos , Peptídeos/efeitos adversos , Conservantes Farmacêuticos/efeitos adversos , Aplasia Pura de Série Vermelha/induzido quimicamente , Insuficiência Renal Crônica/sangue , Seringas/efeitos adversos , Tungstênio/efeitos adversos
15.
Tokai J Exp Clin Med ; 43(3): 90-96, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30191542

RESUMO

OBJECTIVE: This study evaluated the effect of cysteine-stabilized peptide fraction (CSPF) of Morinda lucida leaf on selected kidney function indices in mice. METHODS: Sixty mice were assigned into six groups. Group A served as the control while groups B, C, D, E and F received 31.25, 61.5, 125, 250, and 500 mg/kg body weight of CSPF respectively for 7 or 28 days. RESULTS: Administration of CSPF for 7 and 28 days caused no significant (p>0.05) alteration in kidney-body weight ratio, plasma concentrations of the selected electrolytes, urea and creatinine at all doses compared to controls. However, plasma uric acid concentration was significantly increased (p<0.05) after administration of CSPF for 7 days at doses of 125 and 500 mg/kg body weight while it was significantly reduced (p<0.05) after administration for 28 days at doses higher than 31.25 mg/Kg body weight compared to controls. The activities of Ca2+, Mg2+-ATPase and Na+, K+-ATPases in the kidney and the histology of the kidney remained unaltered (p>0.05) throughout the experimental period compared to controls. CONCLUSION: CSPF may adversely affect uric acid metabolism after prolonged administration.


Assuntos
Cisteína/efeitos adversos , Rim/efeitos dos fármacos , Rim/metabolismo , Morinda/química , Peptídeos/efeitos adversos , Folhas de Planta/química , Proteínas de Plantas/efeitos adversos , Ácido Úrico/sangue , Adenosina Trifosfatases/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Fracionamento Químico , Creatinina/sangue , Cisteína/administração & dosagem , Eletrólitos/sangue , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Peptídeos/administração & dosagem , Peptídeos/isolamento & purificação , Proteínas de Plantas/administração & dosagem , Proteínas de Plantas/isolamento & purificação , Fatores de Tempo
16.
Mar Biotechnol (NY) ; 20(6): 718-728, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30039186

RESUMO

Antimicrobial peptides (AMPs) have attracted attentions as a novel antimicrobial agent because of their unique activity against microbes. In the present study, we described a new, previously unreported AMP, moronecidin-like peptide, from Hippocampus comes and compared its antimicrobial activity with moronecidin from hybrid striped bass. Antibacterial assay indicated that gram-positive bacteria were more sensitive to moronecidin and moronecidin-like compared with gram-negative bacteria. Furthermore, both AMPs were found to exhibit effective antifungal activity. Comparative analysis of the antimicrobial activity revealed that moronecidin-like peptide has higher activity against Acinetobacter baumannii and Staphylococcus epidermidis relative to moronecidin. Both moronecidin-like and moronecidin peptides retained their antibacterial activity in physiological pH and salt concentration. The time-killing assay showed that the AMPs completely killed A. baumannii and S. epidermidis isolates after 1 and 5 h at five- and tenfold above their corresponding MICs, respectively. Anti-biofilm assay demonstrated that peptides were able to inhibit 50% of biofilm formation at sub-MIC of 1/8 MIC. Furthermore, moronecidin-like significantly inhibited biofilm formation more than moronecidin at 1/16 MIC. Collectively, our results revealed that antimicrobial and anti-biofilm activities of moronecidin-like are comparable to moronecidin. In addition, the hemolytic and cytotoxic activities of moronecidin-like were lower than those of moronecidin, suggesting it as a potential novel therapeutic agent, and a template to design new therapeutic AMPs.


Assuntos
Antibacterianos/farmacologia , Peptídeos/farmacologia , Smegmamorpha/metabolismo , Acinetobacter baumannii/efeitos dos fármacos , Animais , Antibacterianos/efeitos adversos , Peptídeos Catiônicos Antimicrobianos/farmacologia , Biofilmes/efeitos dos fármacos , Proteínas de Peixes/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Peptídeos/efeitos adversos , Staphylococcus epidermidis/efeitos dos fármacos
17.
Semin Dial ; 31(5): 440-444, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30009474

RESUMO

Secondary hyperparathyroidism (SHPT), commonly encountered in patients receiving maintenance dialysis, is associated with numerous adverse outcomes, including mortality. Calcimimetics, agents that act on the calcium sensing receptor (CaSR), were designed to overcome limitations in the use of vitamin D sterols to treat SHPT, and have demonstrated efficacy in reducing levels of PTH in randomized trials. Currently available calcimimetics include oral cinacalcet and the recently approved intravenously administered agent, etelcalcetide. While cinacalcet is an allosteric modulator of the CaSR, etelcalcetide acts as a direct CaSR agonist. Etelcalcetide's properties allow it to be administered intravenously thrice weekly at the end of a hemodialysis treatment session. Etelcalcetide has recently been shown to be more potent than cinacalcet in reducing PTH levels. However, etelcalcetide appears, like cinacalcet, to cause gastrointestinal intolerance. Additionally, etelcalcetide, which appears to reduce calcium substantially more than cinacalcet does, can prolong the QTc electrocardiographic interval. While etelcalcetide is very effective at reducing PTH levels, the current climate of dialysis cost containment in the United States may limit its widespread use. This review compares and contrasts the pharmacologic characteristics of cinacalcet and etelcalcetide, discusses the results of clinical trials involving these drugs, and posits implications for their use for clinical practice.


Assuntos
Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Hiperparatireoidismo Secundário/tratamento farmacológico , Peptídeos/uso terapêutico , Calcimiméticos/efeitos adversos , Cinacalcete/efeitos adversos , Humanos , Hormônio Paratireóideo/sangue , Peptídeos/efeitos adversos
18.
Lancet ; 391(10140): 2607-2618, 2018 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-29945727

RESUMO

BACKGROUND: Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the efficacy, tolerability, and safety of treatment with MEDI0382, a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes. METHODS: This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany. We enrolled patients aged 18-65 years with controlled type 2 diabetes (glycated haemoglobin A1c [HbA1c] levels of 6·5-8·5% at screening) and a body-mass index between 27 kg/m2 and 40 kg/m2. An interactive web-response system was used to randomly assign patients to receive MEDI0382 or placebo. Patients were randomly assigned 2:1 in cohorts A-C and 3:1 in cohorts D and E in the MAD portion of the study, and 1:1 in the phase 2a portion. Randomisation was done by a contracted third-party operator who was not involved in the clinical operations of the study. The pharmacists, participants, and study site personnel involved in treating and assessing participants were masked to treatment allocation. Patients received once-daily subcutaneous injections of the study drug at doses of no more than 300 µg for 22 days or less in the MAD portion of the study, and a dose of no more than 200 µg for 41 days or less in the phase 2a portion. The two primary endpoints of the phase 2a portion were the change from baseline to day 41 in glucose area under the curve at 0-4 h (AUC0-4 h) after a mixed-meal tolerance test (MMTT), assessed in all participants who received at least one dose of study drug and whose measurements were taken at baseline and day 41, and change from baseline in bodyweight, assessed in the intention-to-treat (ITT) population. Safety analyses were done in all participants who received any study drug analysed according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02548585. FINDINGS: Patients were recruited between Dec 9, 2015, and Feb 24, 2017. 61 patients were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo). 51 patients were randomly assigned to the phase 2a part, of whom 25 were randomly assigned to MEDI0382 and 26 to placebo. In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC0-4 h post MMTT decreased significantly with MEDI0382 versus placebo (least squares [LS] mean -32·78% [90% CI -36·98 to -28·57] vs -10·16% [-14·10 to -6·21], and the mean difference was -22·62% [-28·40 to -16·85]; p<0·0001). In the ITT population, reduction in bodyweight was significantly greater with MEDI0382 than with placebo (LS mean -3·84 kg [90% CI -4·55 to -3·12] vs -1·70 kg [-2·40 to -1·01] and mean difference of 2·14 kg [-3·13 to -1·31]; p=0·0008). The proportion of patients who had a treatment-emergent adverse event (TEAE) was similar between treatment groups (22 [88%] of 25 in the MEDI0382 group vs 23 [88%] of 26 in the placebo group); gastrointestinal disorders (18 [72%] vs 13 [40%]) and decreased appetite (five [20%] vs none) occurred more frequently with MEDI0382 than placebo. No participants in the MEDI0382 group had a grade 3 or worse TEAE (vs two [8%] in the placebo group). INTERPRETATION: MEDI0382 has the potential to deliver clinically meaningful reductions in blood glucose and bodyweight in obese or overweight individuals with type 2 diabetes. FUNDING: MedImmune.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Hipoglicemiantes/administração & dosagem , Obesidade/tratamento farmacológico , Peptídeos/administração & dosagem , Perda de Peso/efeitos dos fármacos , Adulto , Idoso , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Hemoglobina A Glicada/efeitos dos fármacos , Humanos , Hipoglicemiantes/efeitos adversos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Peptídeos/efeitos adversos
19.
Diabetes Obes Metab ; 20(11): 2690-2694, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29923298

RESUMO

This post hoc analysis of gastrointestinal (GI) adverse events (AEs) from the phase 3 LixiLan-L (NCT02058160) and LixiLan-O (NCT02058147) trials aimed to determine the frequency and timing of nausea, vomiting, and diarrhoea for iGlarLixi, a titratable, fixed-ratio combination of insulin glargine 100 units/mL (iGlar) and lixisenatide, versus iGlar alone or iGlar and lixisenatide alone, in patients with type 2 diabetes uncontrolled with oral antidiabetes drugs (OADs) or basal insulin ± OADs. In iGlarLixi-treated patients, the rate of GI AEs during the initial weeks of treatment was lower versus patients treated with lixisenatide alone (9.6% and 11.7% of iGlarLixi-treated patients in LixiLan-L and LixiLan-O, respectively, vs. 27.5% of lixisenatide-treated patients in LixiLan-O). Beyond day 60, these rates were generally low and similar to those of lixisenatide. These lower rates are likely due to the gradual titration of lixisenatide in iGlarLixi. Median durations of intermittent GI AEs in the iGlarLixi arms were 6.0, 2.0 and 2.5 days (LixiLan-L), and 5.0, 1.0 and 3.5 days (LixiLan-O), respectively. iGlarLixi-associated GI AEs were transient, mostly mild or moderate in severity, and occurred mainly during initial titration.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Gastroenteropatias/epidemiologia , Insulina Glargina/administração & dosagem , Insulina Glargina/efeitos adversos , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Adulto , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Combinação de Medicamentos , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Incidência , Masculino , Período Pós-Prandial , Estudos Retrospectivos
20.
Diabetes Obes Metab ; 20(11): 2680-2684, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29923361

RESUMO

The Healthcare Effectiveness Data and Information Set (HEDIS) measurements assess glycaemic goal attainment in patients with type 2 diabetes, incorporating factors including age and health status. Healthier patients are assigned a glycated haemoglobin (HbA1c) goal of <7% (low-risk [LR]) and individuals aged >65 years or with comorbidities are assigned a goal of <8% (high-risk [HR]). This post-hoc analysis assessed the safety and efficacy of iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL (iGlar) and lixisenatide, in 1898 patients from the phase 3 LixiLan-L and LixiLan-O clinical trials, retrospectively classified as LR (n = 1181) or HR (n = 717). iGlarLixi was more effective in reducing HbA1c than comparators in both LR and HR patients across the LixiLan-L trial (change from baseline, 1.1% vs -0.6% for iGlar in both groups; P < 0.001) and the LixiLan-O trial (change from baseline, LR/HR -1.6%/-1.4% vs -1.3%/-1.2% for iGlar and -0.8%/-0.9% for lixisenatide; P < 0.01). iGlarLixi treatment significantly reduced postprandial glucose in both LR and HR patients (P < 0.001). The incidence of hypoglycaemia did not differ between risk categories in any treatment group.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina Glargina/administração & dosagem , Peptídeos/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Conjuntos de Dados como Assunto , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Combinação de Medicamentos , Feminino , Hemoglobina A Glicada/efeitos dos fármacos , Hemoglobina A Glicada/metabolismo , Humanos , Insulina Glargina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Peptídeos/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
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